The goal of this project is to understand the underlying physiological mechanisms of different involuntary movement disorders. The tools we use include clinical neurophysiological methods such as electroencephalography (EEG), electromyography, and transcranial magnetic stimulation (TMS) and neuroimaging with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). Currently active projects in the Section include studies of tremor, tic, and psychogenic movement disorders. New drugs are needed for treatment of essential tremor. Using tremor accelerometry and clinical tremor testing we have shown that 1-octanol, as a single dose, can be safely used (up to 64 mg/kg) and that it significantly reduces tremor. We are planning to study the pharmacokinetics of octanol. We have been approaching the physiology of tics in several ways. We conducted an event related fMRI study in 10 patients with Tourette Syndrome while spontaneously exhibiting a variety of motor and vocal tics. The results of this study indicate that paralimbic and sensory association areas are critically implicated in the generation of tics, similarly to movements triggered internally by unpleasant sensations as has been shown for pain or itching. We are also using blood flow PET to try to define the anatomy for tic generation. In this situation, we are using a sleep state for baseline so that we can have a state largely free of both tics and urge to tic. The analysis of data shows significant activation of bilateral cerebellum and insula during tic release accompanied by activation of structures already known to be involved in tic pathology such as the putamen, supplementary motor area (SMA) and anterior cingulate cortex. We are also studying the pathology of Tourette syndrome with PET using ligand 11C flumazenil to evaluate changes in the distribution and density of inhibitory GABA A receptors. Using BOLD fMRI, we are attempting to characterize the areas of brain activation associated with involuntary urge phenomena such as the infectious nature of yawning. Using a paradigm to assess the timing of conscious events and EEG analysis, we are seeking to understand the timing of cognitive processes related to the conscious awareness of movement preparation and execution. We are investigating the timing of voluntary movement in normal controls as well as in two patient populations--schizophrenic patients and patients with Tourette's syndrome. We have begun to explore the pathophysiology of psychogenic movement disorders including tremor and myoclonus. We have found that prior to psychogenic myoclonus electroencephalographic focal spectral power changes occur similarly to that seen with voluntary movements, signaling that neural substrates active during the pre-execution phase of voluntary and psychogenic movements may be shared. We are initiating a comprehensive psychiatric assessment of these patients. Patients with restless legs syndrome are being studied through an evaluation of the blink reflex as a probe of dopaminergic function. We are interested in the R2 component and how it is affected by auditory and prepulse inhibition when compared with controls. We have conducted a study looking at persons with paroxysmal kinesiogenic dystonia to characterize the condition better clinically. Simultaneously, there are attempts by an extramural collaborator to find the responsible mutated gene. We have begun to explore the pathophysiology of psychogenic movement disorders including tremor and myoclonus. We are doing EEG and neuroimaging studies trying to identify the parts of the brain responsible for movement initiation.